Unsaturated derivatives of ketonic compounds



Patented Jan. 2, 1945 UNSATURATED DERIVATIVES 0F KETON'IC COMPOUNDS Maurice L. Moore, Detroit, Mich., assignor to Sharp 8; Dohme Incorporated, Philadelphia. Pa., in corporation of Maryland No Drawing. Original application August 8, 1941. Serial No. 405,936. Divided and this application August 19, 1944, Serial No. 550,311

(Ci. zen-239,6)

11 Claims.

useiulness of this type oi'product as intestinal autiseptics i'or combatting and reducingthe can-- on. l The products of thisinvention may be represented by'the'generalt inwhlch u may be hydrogen we e any radical capable of combinlngwith a'carboiyl icai'to form a carboaylatgsuch as the metalsis me alkaiilmetals sodium. iithlumj-l the'like; the alkaline eartbsj a s calcium. mfl ir mm. ba i m fl nu nr. op e s d. iron, bismuth and the alpl radical, a nitrogenliase as'iin nonilfin and correspbndinz radicals oi flkyiamiries and alir anolamines and thell ke: and His there'sidue or an unsaturated A phfl-iii .pdlycarbosylic acid. stripped oi! its carbd xyi groups; and'r may be hydrogen as well as any of the radicals rem,- sented by M and when M is mlyvalent T'n'isy represent some or all of the valences oi M not satisfied by the single group to which M is iilustratedas being' attached; and 1: may be heroes well as any whole number up to tour. whereby the grouping -(--.CoQ-.) ..T

represents the carboxyl and the carboxylate groups over two from any polycarboxylic acid having more than two carbolwi p and is a small number equal to the valence 01' M when n is zero and also when each occurrence oi radia] T is either hydrogen or any other monovalent radical and also when each occurrence oi the radical '1 (whether monoor P LY- s diftion of -organisms causing intestinal iii-'- ierent from the-radical M; and since M and '1 may be separately polyvalent, m may be one when all 01' the carbosyl groups in the carboxylacyl radical satisfy all oi the valences of such polyvalent radicals M-and T; and E may be hydrogen as well as an-alkyl radical having, for mmple, from one to about eight or more carbon atoms as well as an aryl radical such as phenyl (unsubstituted as well as substiuitedl and Ar is an and radical (havin as shown in the general iormula, a valence linked to nitrogen and a valence linked to sulfur) sueh-asthe phenyl (unsubstitutedas Welles-substituted, for example, havlnglnitro. amino; aliql carboni, sulionic acid, hydroxy new with t e 41m d.- QFPWWQW and straight or branched chain; phenyL-ihglqgen such aschlcrine and theiike mbstltucntsl'gand P a'lnm ieflrema-mum stitutedh radicals: and o mayhahydrosedjs i 8) weli-asdmalky1-rad icai.saturated-orimsa' ted,-

o m nlea e hril-s rl, PNDYLJEUQ ami. m mm and t e li agcr decr l odecyl. hexadeeyl and the like and cyclope ntenyi or cycicbexyl gas well as an aralkyl radical-sea :5 mmrmd the-like-,,as-well as an aryl-radical ,as

'phenyl (unsubstituted as; well as .asnoted for. Ar above) .-naphthyi (similarly stifiutedns well Ila-memes) meme li ki-and r l um wa r' rd w fllis an alkyl- (straight orbranched chain or cycli l radical. saturatedgr, unsatu rated, tor-example. methyl, ethyl. prdpylgbutyl. amyl, ally], hexyl, heptyi, oct'ylandtliellkq'or decyl. dodecyl.=hexadecyl and the like, or .cyclo pentenylor cyclohexanyl and the lilregasjlweli as anaryl radical as phenyl (substituted as well 5 unsubstituted, as noted (or Al above), to'lyl, .dlphenyl, naphthyl (all similarly. unsubstituted as, well as substituted). as well asan aralkyl radical is bell!!! and the like. or a nitrogen containing radical as nitro and amino (unsubstituted and substituted as acyland alkyl-l and an oxygenated radicaL-tor exampie. hydroxy. alkoxy such as methoxy. ethoxy. propoxy, and carbalkoxy such as carbmethoxy, carbcxyl. and halo-alkyl as chiorethyi and the like, and halogen, for example. chlorine and bromine.

The'carboxyacyl group (remaining group when the lrydroxy group is removed from only one oi the at least two carboxyl groups of the po ycarboxylic acid) may be derived from any desirable unsaturated aliphatic polycarboxylic acid.

for example, those having at least four carbon atoms and further particularized by maleic and citraconic fmethylmaleic) acids and their respective isomers, furnaric and mesaconic (methylfumaric) acids.

Other unsaturated aliphatic polycarboxylic acids from which the carboxyacyl radical may be derived are the tribasic unsaturated acids exem plified by aconitic acid and derivatives thereof as those in which any of the methylene or chain hydrogens is replaced by any desirable substituent.

The invention also includes the preparation of these carboxyacylaminoaryisulfonamldothiazolones which are made by heating the desired polycarboxylic acid, its anhydrlde, or an ester, such as an alkyl ester, or a monohalide, such as the monochloride or a monochloride of the ester. thereof with, for example, the desired aminobenzenesulionamidothiazolone, either merely togather or in an inert reaction medium such as an inert solvent, and as in the latter case separating the desired end product or, as in the case of the use of the ester. liberating the end product by hydrolysis, and in any case, where necessary. subiecting it to purification as by recrystallization. With the unsaturated aliphatic acids having four and five carbon atoms in the chain, the desired anhydride is taken as the starting material, while with the acids having over five carbon atoms in the chain, the free acid may be heated directly with the selected aminoarylsulionamidothiazolone. Ii desired. the monohalide of the ester of thiazalone.0.9 gram of maleyl anhydrlde was added to a boiling suspension of-2 grams of 2- sulfaniiyl-5-ethyl-4 thiazolone in '50 cc. of alco-' he] and the boiling was continuedtor about flve minutes when'the solution was complete, The reaction solution was then diluted andchilled. The desired 2-N-maleylsu1fanilamido-5 ethyi4- thiaaolone after fllterlng, upon' recrystallization from d lute alcohol, melted with decomi osition at 160-165 c.

By replacing the maleic' anhydride in the'above example bry'the equivalent quantity oi thepos's'ble inner anhydrl'de's of other acid derivatives, such as citraconic acid anhydride and the like, corresponding carboxyacyls uli'anilvlthiazolone's are obtained. for example. '2 all citraconylsulfanilamido-5,5-diethyl-4-thiaaolone, 2-N citraconylmilianilamido fi-ethyl-s-thiazolone.

The carboxyacylaminoarylsulionamidothiaroiones derived from the transform derivatives may be obtained by .the reaction or the desired sultanilamidothia'zolones with an equivalent quantity of a corresponding monochlorlde-ester of such derivative, with little or no heating, for example, with the equal quantity oi the monochloride oi the ethyl ester oi, for example. iurnaric or mesaconlc acid. among which compounds of the invention are:

The

carboxyacylaminoarylsulionamidothiazolone in which the carboxyacyi radical is derived from an aliphatic poiycarboxyiic acid having more than five carbon atoms in the chain, are obtained, for example, by mixing equlmolecular quantities of the desired sulianiiamidothiazolone and the desired polycarboxylic acid and heating the mixture at between about -155" C. for about an hour and then treating the reaction product in about one or one and one-half liters per mole of acid used of an about 10% solution of ammonium hydroxide to separate the insoluble, undesired by-products. The latter are then filtered 011 and the filtrate is neutralized with dilute hydrochloric acid yielding the desired carboxyacylaminoarylsulfonamidothiazolone which may, if desired, be purified by redissolving in dilute ammonia and slowly precipitating with dilute hydrochloric acid. Such compounds and those obtainable from the amino and hydr0xy-sub-.

stituted derivatives of the acid are illustrated by:

2-N*-aconitylsulianilamido-4-thiazoione,

2-N*-aconitylsulianllamido-fi-ethyl-4- thiazolone.

and

2-N-aconitylsulfanilamido-5,5-diethyl-4- thiazolone.

Furthermore, by replacing the Z-sulfanilamido- 5-ethyl-4-thiazolone in any of the examples and in any of the modifications oi. the examples as Just hereinabove and hereinbelow included in the various paragraphs following the example, by 2- sulianilamldo-4-thiazolone or by any thiazolone nuclearly (in the 5-positlon) substituted aminophenylsulfonamido-4-thiazolone having any of the substituents at the type represented by El and R: in the general formula of the products of this invention, there are obtained the-correspending carboxyacylsultanilamido- 4 -thlazolone and carboxyacylsuifanilamido 4 thiazolones in which there are one or two substituents in the 5- positlon on the thiazolone-nucleus. Thus, by-

varying the aminoaryisulfonamido-4-thiazolone '1 or the; sulianilamldo-i-thiazolone starting materiaLand employing corresponding materials in which'the thiaaolone-nucleus is either non-substituted or substituted as Just above indicated. there areobtalned the corresponding compounds.

To'obi-ain the compounds of the invention in the aminoarylsuionamidothiazolone starting material employed ,to produce the thiazole or thiazolone-nuclearly substituted compounds of the invention as shown above is alkylat'ed or aralkylated or aryiat'ed by reactionwith the necessary suitable nlkylatlng, aralkylating or arylating agent to attach to the sulion'ainido nitrogen the. desired positive radical. Alkylating agents such.

as an alkyl halide, as methyl chloride or ethyl chloride or. bromide, or an all vl sulfate as an alkyl sulionate, and the like, may be employed to replace the hydrogen represented by G by the desired alkyl radical, and by using the corresponding araikylating 0r arylating agent. by the desired aralkyl or aryl radical. By reacting the thus obtained aminobenzenesulionalkyl-, araliryl-, or aryl-amido-4-thiazolone with the desired polycarboxylic acid, or anhydrlde or ester thereof. there is obtained any desired product of the invention having a positive radical other than hydrogen for the element G in the general formula. for example, the Z-N carboxyacyIaminobenzenesulfonalkylamidothiazolones.

By replacing the carboxyacyl group in any of the above compounds including also the thiazol uclearly substituted, as well as the N -subsmuled ounds of the invention, by the carbgxyacyl radical derived from any other polyc rboxyllc acid of the type hereinabove disclosed. by ying any suitable one of the above described rocedures, the corresponding compound of the invention with the corresponding different carboxyacyl radical is obtained. Also. by replacing the 2-(aminobenzenesulfonamido) -4-thiazolone or nucleariy-substituted thiazolone as a reactant in any of these procedures. there is obtained the corresponding carboxyacylaminoaryisulionarnido-4-thiazolone containing any desired carboxyacyl radical of the type herein indicated as well as any N -substituent or any one or two desired substituents in the S-posltion on the thiazolonemucleub.

From the various exemplifications oi the compounds of the invention. there is seen that they may be generally referred to as carboxyacylaminoarylsulfonyl derivatives of aminothiazolanes. in which the thiazolone portion, as indicated by the thiazclone nucleus and the elements R1 and R1 in the general lormula. is referred to lly as "thiazolones" to embrace not only those compounds in which the thiazolone radical is derived from 4-thiazolone itself, but also those in which the thiazolone portion is derived from the s-thiazolone nucleus mono or di-substltuted in the 5-posltion, and in which derivatives, the amino radical through which the thiazolone portion is attached to the sulfur. is either unsubstituted or substituted by a positive radical.

The products of the invention, in which M and T of the general formula are hydrogen are senerally practicahly water soluble, are usually neutral compounds, which become very substantially soluble in water when the free carboxyl "group or groups in the product is converted to the carboxylate form by the use of the equivalent amount of ammonium hydroxide or an mine or alkanolamine or of sodium bicarbonate. Thus, the compounds in which M and T are hydrogen may exhibit a solubility in water within about five or up to about ten per cent, whereasthe carboxylate form of the same compound may have a solubility up to about fifty per cent and even higher. I The carboxylate form of any of the compounds of the invention may be prepared, for eaample, by adding to a small amount or water an excess of the compound over its solubility in and dissolving the excess by stirringin a suflloient quantity of. for example, anhydrous sodium bicarbonate. The solution is preferably filtered and from the filtrate the highly soluble sodium salt can be isolated. for example, by adding an equal volume of alcohol and pouring the resulting solution into about volumes of acetone. The substance thrown out of solution is permitted to settle and the supernatant liquid withdrawn and the residue preferably treated several times with fresh acetone. After decanting the acetone from the last treatment, the resulting desired sodium salt may be dried preferably under vacuum.

Other metal carboxyiate salts of the compounds such as the copper, gold. iron and bismuth salts and the like may be obtained by reacting the alkali metal salt, preferably in aqueous solution, with a suitable soluble salt of the metal. the carboxyiate salt of which is desired. The desired carboxylatesalt is obtained by resulting double decomposition.

These compounds, applicable as intestinal antiseptics. exhibit such activity by the attachment to the various nuclear portions of the ompound, of substituents the introduction of which into the basic nuclei leaves the compound substantially non-toxic. Similarly, the metallic element in the compounds used as intestinal antiseptics are such that their inclusion in the compound introduces no toxic characteristic.

In general, the carboxyacy yl derivatives of the aminothiazolones, in which the carboxyacyl radical contains four carbon atoms in the aliphatic chain. are especially effective as such intestinal antlseptics for it is possible to build up a high concentration of them in the intestinal tract and without a simultaneously high blood level and yet with substantially no noticeable indication of toxic symptoms. Among these particularly effective compounds are such as those in which the carboxyacyl radical is obtained from maleic, citraconic, fumaric and mesaconic acids and their substituted derivatives. The N -carboxyacyi products of the invention show distinctive activity.

The various compounds, used as intestinal antlseptics, are administered orally. either in the form of tablets, capsules or powders of the solid material or as solutions 01' any desired concentration, exceeding, if desired, 50%.

In the specification and claims the carboxyacyl radical, as hereinabove defined, derived from specific polycarboxyiic acids herein named. is designated by replacing, the terminal "-ic" in the name of the acid by the ending "-yl" as, for example, maleyi, fumaryl and mesaoonyl carboxyacyl radicals and the like, derived respectively from maleic, fumaric and mesaconic acids and the like.

The term "benzene" as used in the specii'icatin and claims, for example, in the expression (carboxyacylaminobenzencsulfonamido)-4- clones" covers the divalent residue orm-5M one free valence of which the carboxyacylamino mup is linked and to the other freevalence of which the sulfur of the sulionyl group is-attached so that there are only those two subsfltujeritg, on;. the benzene ring. On the other hand, thdlterm "phenyl" as used in this specification and claims; 1 for example, in 2-(carboxyacylaminophenylsulfonamido) -4-thiasolones" is generic and includes this divalent residue CHi as lust hereinabove defined with respect to the term benzene (otherwise referred to Is the non-substitutcd-phenyl divalant g oupl, as well-ups to substituted phenyi-mucleus in which one or m re of theremainin'g four hydrogen atoms 'be' replaced if by an additional substitucnt on the rings; The expression carboxylates employed in any of the claims embraces those smups resulting from replacing the hydrogen of a carboiwi group .with any other grouping capable of combinin with a carboxyl radical to form a carboxylai'e such as the various metals and the like, or an alkyl radical or a nitrogen base and the like oi the type hereinabove described at page 1. column 1, lines 25 through 33, and prepared in the manner hcrelnabove described beginning at page 8, column 1, line 49, and running through line 73.

This application is a division of my copending :gpiicaticn, Serial No. 405,935, flied August 8.

I claim:

1. 2 carboxyacyiamlnoarylsulfonamido-4-thiazolones, in which the carboxyacyl group is unsaturated aliphatic.

2. At least one 2-(carboxyacylamlnophenylsui. ionamidol-i-thiazoline, prepared for use as a therapcuuc or the group ing of those of the formula and the carboxylatcs thereof, in which ZR is a carboxyl containing group linked to the (3 0 by a carbon atom of the radical R; R is the residue of an unsaturated aliphatic polycarboxylic acid stripped of its carboxyl groups; E and G are each separately and independently a member of the class consisting of hydrogen, alkyl, aralkyl and aryl radicals; and the thlazolone ring together with the elements R1 and R: attached to the S-carbon on the ring represents a member of the class consisting of the thiazolone and nuclearly substituted thiazolone radicals.

3. 2 (N carboxyacylaminophenylsulfonamido)-4-thiaz0loncs, in which the carboxyacyl group is unsaturated aliphatic.

4. 2 (N maleylamlnophenylsulfonamldo) -4- thlazoloncs.

5, 2 (carboxyacylamlnobenzenesullonamldn) 4-thiazolones, ln which the carboxyacyl group is unsaturated aliphatic.

6. 2 (N-carboxyacylamlnobenzenesulfonamldo) -4-thiazolones. In which the carboxyacyl group is unsaturated aliphatic.

'7. At least one compound of the group conslstmg of 2-IN-maleylaminophenylsulfonamldol-q-thiazolones and the carboxylates thereof.

8. 2-N-maleylsulIan1lamldo-4-thiazolones.

9r 2-N-maleylsulfanllamldo-5-ethyl-4 -thlszoloncv l0. 2-N-aconitylsu1lanllamldo 5,5 diethy1-4- thiazolone.

ll. 2 N -carboxyacylamlnoarylsulfonamldo- 5,5-dl8lkyl-4-Lhl3-ZO1OHES, in which the carboxyacyl group is unsaturated aliphatic.

MAURICE L. MOORE.

CERTIFICATE OF CORRECTION.

Patent No. 2566,6141.

January 2, 191 5.

HAU RICE L MOORE It is of the above numbered pate and column, line k9, for

uinn, line 56, 52, for this-sols claim 2, for thiazoline latent should be read form to the record of the case S igna (Sean 4.} ertified that or hereby c iring correction as follows.

nt roqu hydroxy road s for transform read tran read --thiazo1one--; page 5,

" read --chiazo1one-- with this correction more in the Patent Office.

d and sealed this 7th day of A or appears in the printed speoi in that the same may conugust, A. D- 9 15- Acting Commissioner of Patents.

therapcuuc or the group ing of those of the formula and the carboxylatcs thereof, in which ZR is a carboxyl containing group linked to the (3 0 by a carbon atom of the radical R; R is the residue of an unsaturated aliphatic polycarboxylic acid stripped of its carboxyl groups; E and G are each separately and independently a member of the class consisting of hydrogen, alkyl, aralkyl and aryl radicals; and the thlazolone ring together with the elements R1 and R: attached to the S-carbon on the ring represents a member of the class consisting of the thiazolone and nuclearly substituted thiazolone radicals.

3. 2 (N carboxyacylaminophenylsulfonamido)-4-thiaz0loncs, in which the carboxyacyl group is unsaturated aliphatic.

4. 2 (N maleylamlnophenylsulfonamldo) -4- thlazoloncs.

5, 2 (carboxyacylamlnobenzenesullonamldn) 4-thiazolones, ln which the carboxyacyl group is unsaturated aliphatic.

6. 2 (N-carboxyacylamlnobenzenesulfonamldo) -4-thiazolones. In which the carboxyacyl group is unsaturated aliphatic.

'7. At least one compound of the group conslstmg of 2-IN-maleylaminophenylsulfonamldol-q-thiazolones and the carboxylates thereof.

8. 2-N-maleylsulIan1lamldo-4-thiazolones.

9r 2-N-maleylsulfanllamldo-5-ethyl-4 -thlszoloncv l0. 2-N-aconitylsu1lanllamldo 5,5 diethy1-4- thiazolone.

ll. 2 N -carboxyacylamlnoarylsulfonamldo- 5,5-dl8lkyl-4-Lhl3-ZO1OHES, in which the carboxyacyl group is unsaturated aliphatic.

MAURICE L. MOORE.

CERTIFICATE OF CORRECTION.

Patent No. 2566,6141.

January 2, 191 5.

HAU RICE L MOORE It is of the above numbered pate and column, line k9, for

uinn, line 56, 52, for this-sols claim 2, for thiazoline latent should be read form to the record of the case S igna (Sean 4.} ertified that or hereby c iring correction as follows.

nt roqu hydroxy road s for transform read tran read --thiazo1one--; page 5,

" read --chiazo1one-- with this correction more in the Patent Office.

d and sealed this 7th day of A or appears in the printed speoi in that the same may conugust, A. D- 9 15- Acting Commissioner of Patents. 

